D-Amino Acids and Classical Neurotransmitters in Healthy and Type 2 Diabetes-Affected Human Pancreatic Islets of Langerhans

The pancreatic islets of Langerhans are clusters of cells that function as endocrine units synthesizing and releasing insulin and a range of additional peptide hormones. The structural and chemical characteristics of islets change during type 2 diabetes development. Although a range of metabolites including neurotransmitters has been reported in rodent islets, the involvement of these cell-to-cell signaling molecules within human pancreatic islets in the pathophysiology of type 2 diabetes is not well known, despite studies suggesting that these molecules impact intra- and inter-islet signaling pathways. We characterize the enigmatic cell-to-cell signaling molecules, D-serine (D-Ser) and D-aspartate (D-Asp), along with multiple classical neurotransmitters and related molecules, in healthy versus type 2 diabetes-affected human islets using capillary electrophoresis separations. Significantly reduced D-Ser percentage and gamma-aminobutyric acid (GABA) levels were found in type 2 diabetes-affected islets compared to healthy islets. In addition, the negative correlations of many of the signaling molecules, such as D-Ser percentage (r = 0.35), D-Asp (r = 0.32), serotonin (r = 0.42), and GABA (r = 0.39) levels, with hemoglobin A1c (HbA1c) levels and thus with the progression of type 2 diabetes further demonstrate the disruption in intra- or inter-islet signaling pathways and suggest that these cell-to-cell signaling molecules may be potential therapeutic targets.